Alcoholics are known to be very susceptible to infections. We studied the effects of alcohol on the immune system using male, Sprague-Dawley rats (normal and adrenalectomized) made dependent upon alcohol using a liquid diet supplemented with ethanol or inhalation of ethanol vapors. Immunization prior to and during the administration of ethanol was performed to test the ability of the immune system to mount a response to a novel challenge. Ethanol administration resulted in a loss of lymphocytes in the spleen, thymus, and peripheral blood regardless of the route of administration (intubation or inhalation). Intubation of ethanol resulted in a decrease in the ability of the remaining spleen and peripheral blood lymphocytes to respond to non-specific mitogens, while no such decrease was noted in the remaining splenic lymphocytes of animals treated with ethanol by inhalation. The ability to respond to immunization with T-cell dependent antigen SRBC was decreased by ethanol administration by intubation while immunization with the T-cell independent antigen TNP-ficol produced no obvious decrease in the ability of the immune system to respond. Serum corticosterone levels were analyzed with two peaks noted -one after two days of ethanol administration and the other on the day of withdrawal in normal rats. Adrenalectomized rats showed a decrease in cell number in peripheral blood, thymus and spleen and in the ability to mount a response to non-specific and specific challenges (mitogens and SRBC immunizations) with the administration of ethanol, although the magnitude of cellular and functional loss was less than in the intact animal. IL-2 production was monitored during ethanol administration and was found to be enhanced with respect to control at the same time that functional activity was lowest. There was some indication that the T-helper subset was the first T-cell subset affected by the administration of ethanol. Further investigations are in progress to develop other models of ethanol administration to study the contributing mechanisms of alcohol-induced alterations in the immune system.